| The cell redox state is critical for maintaining energy metabolism and antioxidant responses. Disruption of redox homeostasis results in compromised cell integrity and is associated with diseases including type I diabetes and Alzheimer's disease (AD). Therefore, it is imperative to understand how imbalances in the redox state contribute to disease pathogenesis. The redox ratio is dependent on the levels of oxidized and reduced nicotinamide adenine dinucleotide (NAD). Although NAD is not consumed in these reactions, there are enzymes that utilize NAD as a substrate including poly(ADP)ribose polymerase 1 (PARP1), sirtuin 1 (SIRT1), and CD38. Interestingly, Cd38-/- tissues have higher levels of NAD, suggesting that CD38 regulates NAD homeostasis. We hypothesize that CD38, by modulating NAD levels, alters oxidative stress responses and the activities of other NAD consuming enzymes.;In vitro, mouse embryonic fibroblast cells deficient in CD38 have increase NAD, NADP, NADH, and NADPH levels. In response to genotoxic stress, Cd38-/- cells exhibit higher levels of intrinsic superoxide and reactive oxygen species and are more susceptible to H2O2 induced apoptosis. Due to increase intrinsic oxidative stress, Cd38-/- cells undergo premature p16ink4a mediated senescence.;The role of CD38 in oxidative stress was investigated in vivo using STZ, a DNA alkylating drug that targets pancreatic beta-cells. Following STZ exposure, Cd38-/- mice are more prone to beta-cell damage and diabetes with subsequent drops in nicotinamide and NAD(P(H)) levels. Cd38-/- mice have increase 8-hydroxydeoxyguanosine staining in beta-cell nuclei, double stranded DNA breaks, and hyperactivation of PARP1. Treatment with nicotinamide maintained NAD levels and rescues Cd38-/- mice from diabetes.;In an AD model, APP.PS.Cd38-/- mice exhibit reduced Abeta plaque formation and improvement in learning compared to APP.PS counterparts. Brains of APP.PS.Cd38-/- mice have higher levels of NAD and increased SIRT1 activity, which has been shown to protect against AD pathology.;Collectively, our results demonstrate that CD38 is protective against ROS by regulating nicotinamide and subsequent NAD(P(H)) levels that are critical for redox homeostasis. Additionally, CD38 deletion regulates PARP1 and SIRT1 activity, impacting disease progression. Importantly, this study identifies a novel role for CD38 in oxidative stress and may provide potential targets for prevention of various diseases including diabetes and AD. |
